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Growing evidence reveals increased infiltration of myeloid cells with substantial heterogeneity, raising the question of how Ly6Chigh monocyte-derived macrophages in the stroke brain adapt to the ischemic environment. Here, by combining analysis of stroke patient samples with in vivo and in vitro murine studies and single-cell transcriptomic profiling, we identify hypoxia-inducible lipid droplet-associated protein (Hilpda)\/hypoxia-inducible protein 2 (HIG2) as a critical mediator of anti-inflammatory property of Ly6ChighLy6Glow monocyte-derived macrophages in the stroke brain. Mechanistically, HIG2 promotes phosphatidylcholine synthesis via Hif1\u03b1-dependent transcriptional regulation of choline kinase \u03b1, initiating lipid metabolism reprogramming that underpins the anti-inflammatory phenotype of Ly6ChighLy6Glow monocyte-derived macrophages in the ischemic brain after stroke. Intranasal delivery of recombinant HIG2 protein improves neurological outcomes after stroke. These findings suggest that targeting HIG2 might represent a novel immunometabolic strategy to mitigate poststroke neuroinflammation.<\/jats:p>","DOI":"10.1084\/jem.20242025","type":"journal-article","created":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T13:47:03Z","timestamp":1773841623000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Hypoxia-inducible protein 2 mediates metabolic adaptation of Ly6ChighLy6Glow monocytes after stroke"],"prefix":"10.1084","volume":"223","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-1440-0440","authenticated-orcid":true,"given":"Weijie","family":"Chen","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0220qvk04","id-type":"ROR","asserted-by":"publisher"}],"name":"Renji Hospital, Shanghai Jiao Tong University School of Medicine 1 Department of Anesthesiology, , 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